The feline major histocompatibility complex (MHC) has been studied using molecular techniques as an approach to comparative genome organization of this important gene cluster. The MHC encodes two types of antigen- presenting molecules for T-cell receptors (class I and class II antigens) and control immune responses to various pathogens and tumors. In the human MHC, over 80 genes have been identified in an approximately 4,000 kilobase region on the short arm of chromosome 6. The feline MHC region has about 20 class I genes, at least 2 alpha chain coding genes and 3 beta chain coding genes for class II molecules, and is located on a centromeric region of chromosome B2, which shows syntenic homology to human chromosome 6 and mouse chromosome 17. Complete sequence analyses of 14 class I cDNA clones isolated from 3 species which represent 3 major taxonomic lineages of Felidae (domestic cat, ocelot, and cheetah) reveal 4 major factors for generation of polymorphic feline MHC class I molecules, which include (i) gradual accumulations of spontaneous mutations, (ii) negative selection pressure against mutational changes in framework structure of class I molecules, (iii) positive selection pressure in favor of generation and maintenance of polymorphic domains, and (iv) inter- and intra-locus DNA recombination to exchange short polymorphic nucleotide segments. Moreover, similar or identical polymorphic sequence motifs were identified among class I sequences of three feline species and other mammalian species, suggesting that these four processes are extremely slow and prototypes of polymorphic class I molecules could be generated before separation of major mammalian species.